In their review article entitled “Insulin-like growth factors and neoplasia”, the authors did a great job in describing the hypothesized role of insulin-like growth factor 1 receptor (IGF1R) in carcinogenesis. However, the authors seem to discount the potential effect of IGF2R.
In a case–control study of oral epithelial cancer1, we found a strong independent direct effect for a short-tandem-repeat polymorphism — IGF2R-167 (also referred to as IGF2R-B2A2) — probably indicating a non-functional variant. Heterozygous individuals with the above genotype had a 2.7-fold increased risk of oral cancer compared with individuals with other genotypes (odds ratio, 2.7; 95% confidence interval, 1.16–6.48), controlling for major confounders. The identification of such a direct effect was unexpected, and we used caution in interpreting the findings.
As several authors have described similarities in the pathogenesis of oral and lung malignancies and the sharing of common risk factors, we decided to test IGF2R-167 in lung cancer. A new case–control genetic epidemiological study of lung cancer was designed and implemented to test the hypothesis that the IGF2R-167 genotype is associated with increased risk, controlling for tobacco use. Again, results indicate a significant and independent association among the genotype and non-small-cell lung cancer risk in Caucasian men (A.I.Z., V.G.G. and A. Kotsinas, unpublished observations). Our findings are summarized in Table 1.
The possible mechanism underlying the above association might be the lack of sufficient IGF2R expression, which would allow the prolonged stimulation of lung epithelial cells by growth factors that are normally turned over by the receptor.
Recently, an association has also been shown in breast cancer cell lines with different invasive potential and was attributed to a sequence difference located in the 3′ untranslated region (UTR) of IGF2R, which affects the post-transcriptional stability of the receptor2. Surprisingly, we realized that this 3′ UTR coincides with the location of the IGF2R-167 genetic locus and that the described difference between the cell lines represents the presence of distinct allelic variants of this polymorphism. These data indicate that the 'proper' function of the IGF2R depends on the length of this 3′-UTR polymorphism2. Therefore, it seems that in a normal population, high-frequency alleles reflect the optimum length for normal levels of expression, whereas low-frequency alleles are negatively selected, probably because of “attenuated” functional capacity. In this case, the functional links between IGF2R and activation of transforming growth factor-b1, degradation of IGF2, mediation of the action of the retinoids and trafficking of cathepsins B and D, might be influenced by the status of this polymorphic locus, markedly affecting vital cellular functions and predisposing even more to inherited pathological conditions, including malignancies.
In summary, two independent studies confirmed a strong association between IGF2R-167 short-repeat-polymorphism and oral or non-small-cell lung cancer risk.
Zavras, A. I. et al. Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans. Cancer Res. 63, 296–297 (2003).
Xie, S. & Kang, J. X. Differential expression of the mannose 6-phosphate/insulin-like growth factor-II receptor in human breast cancer cell lines of different invasive potential. Med. Sci. Monit. 8, BR293–BR300 (2002).
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Zavras, A., Douglass, C. & Gorgoulis, V. The role of IGF2R in carcinogenesis. Nat Rev Cancer 5, 836 (2005). https://doi.org/10.1038/nrc1387-c1